苯并咪唑类聚腺苷二磷酸核糖聚合酶抑制剂的合成及初步活性研究

目的 设计合成一系列苯并咪唑类衍生物,并测定其聚腺苷二磷酸核糖聚合酶(PARP)抑制活性.方法 以3-硝基邻苯二甲酸酐为基本原料,经开环、Hofmann重排、酰胺化或酯化、还原得到邻二氨基苯化合物,再与相应的苯甲醛及其衍生物环合得到目标分子;采用体外抑酶试验初步筛选目标分子的PARO抑制活性.结果与结论 合成了22个苯...

Synthesis and evaluation of benzimidazole derivatives as poly(ADP-ribose) polymerase inhibitors

Poly（ADP-ribose） polymerases（PARPs） are a large enzyme family which consists of at least 17 members.These enzymes are implicated in multiple cellular processes through catalysis of the addition of ADP-ribose polymers on various acceptor proteins.PARP-1,the most abundant isoform which can be activated by DNA damage,plays an important role in the repair of DNA single strand breaks（SSBs） under normal circumstances.However,PARP-1 can also contribute to resistance after cancer therapy due to its DNA repair activity.Thus PARP inhibitors have been pursued for many years as chemo/radiotherapy sensitizers in cancer treatment.Besides being used in combination,PARP inhibitors may also be applied as monotherapy in some specific cancer types with synthetic lethality as the main mechanism of action.There are currently at least six compounds being investigated in clinical trials,including BSI201,AZD2281,ABT888,MK4827,AG014699,and INO1001.NU1085,developed by the University of Newcastle,has been used as a benchmark of PARP inhibitors due to its potent activity and other good features.We used NU1085 as the lead compound,attempting to find more desirable PARP inhibitors through structural modification.Docking between PARP-1 and the designed molecules showed that introduction of lipid soluble groups at 4′-position might improve the PARP inhibitory activity.In addition,a series of 4-carborsylate derivatives were also designed and synthesized to find novel PARP inhibitors.Twenty-two benzimidazole derivatives were synthesized in all,starting with 3-nitrophthalic anhydride which underwent ring-opening,Hofmann rearrangement,amidation or esterification,and reduction to give diamino compounds.Condensation of the diamino compounds with benzaldehyde or its derivatives afforded the target compounds.All the target compounds were structurally confirmed by 1H-NMR,IR and MS and seventeen compounds were novel ones.The following poly（ADP-ribose） polymerase inhibitory activity assay in vitro showed that most of the target compounds exhibited potent PARP inhibitory activity,and structural modification at 4′-position resulted in increased potency.Compounds Ⅰ2,Ⅱ2,Ⅱ3,Ⅱ8,Ⅱ10 displayed single digit nanomolar inhibition of PARP-1 with IC50=1.5,3.32,2.89,6.42 and 4.26 nmol · L-1,respectively.